The treatment of inflammation and the pain, swelling, fever, and the like, associated with inflammation using anti-inflammatory agents is commonplace. Regardless of the type of pain, whether acute as in stings, ankle sprains, broken bones, and the like, or chronic from disease states as in neurodegeneration, arthritis, septic shock, fibromyalgia, interstitial cystitis, migraine, neuropathic pain syndromes, reflex sympathetic dystrophy, vulvar vestibulitis syndrome, and the like, pain arises from inflammation and the inflammatory response. The inflammatory response is a process involving the release of various chemical mediators.
The inflammatory response is a cellular cascade of these chemical mediators operating in a complimentary and synergistic fashion. One class of potent inflammatory mediators is the arachidonic acid metabolites that include various thromboxanes, leukotrienes and prostaglandins. Thromboxanes, leukotrienes and prostaglandins are released from cells in response to injury and infection, activate local nerve receptors and nerve terminals, and are associated with increases in vascular permeability (edema), blood cell adhesion, and temperature.
A simplification of a process through which a prostaglandin is created is as follows: Injury occurs to tissue and the cells within; Blood cells (basophils, mast cells and platelets) release inflammatory mediators (e.g., serotonin, histamine); subsequent to the binding of these mediators with nerve receptors, the adjacent nerves and nerve endings (i.e., C-fibers and A-delta fibers which carry pain impulses to the brain) release inflammatory peptide proteins (e.g., Substance P, Calcitonin, Calcitonin Gene Related Peptide), concomitantly clotting factors in the blood produce and activate inflammatory mediator peptide proteins (e.g., Neurokinin A, Bradykinin, Kallidin and T-kinin); these peptide proteins activate phospholipids embedded in the cell membrane causing the release of Lipid Peroxides (i.e., Archidonic Acid); cyclooxygenase, a cell membrane bound enzyme produced during cell inflammation, oxidizes the lipid peroxide to synthesize prostaglandin.
Many of the currently available analgesic agents (i.e., corticosteroid anti-inflammatories and non-steroidal anti-inflammatories) function by inhibiting the production of the arachidonic acid metabolites, either selectively, through inhibiting cyclooxygenase 2, or non-selectively through inhibition of both cyclooxygenase I and 2. Unfortunately, many anti-inflammatory products have acute and chronic safety issues that limit their application. For example, the non-steroidals inhibitory activity with regard to cyclooxygenase may create problems associated with gastric and renal toxicity, such as ulcers and serious complications such as bleeding, perforations, and obstructions. Further, a user of non-steroidal anti-inflammatory agents may be required to co-administer a gastric protectant when administering the anti-inflammation agent in order to avoid the harmful effects.
Creatine has been studied as an alternative to the use of corticosteroids and non-steroidal anti-inflammatory agents. Creatine has been shown to possess anti-inflammatory activity. See Khanna, N K and Madan, B R. Studies on the anti-inflammatory activity of creatine. Arch Int Pharmacodyn Ther 231(2): 340-350, February 1978, which is herein incorporated by reference in its entirety. This activity has been shown orally effective in suppressing the inflammatory responses produced by carrageenan, 5-hydroxytryptamine, nystatin and formaldehyde. See Madan, B R. and Khanna N K. Effect of creatinine on various experimentally induced inflammatory models. Indian J. Physiol Pharmacol 23(1): 1-7, January-March 1979, which is herein incorporated by reference in its entirety. Subsequent studies have further confirmed the anti-inflammatory activity of creatine alone and in combination with other anti-inflammatories, See Khanna, N K. and Tahashildar, J. Anti-inflammatory activity of Creatine and Indomethacin Drug Mixture in Rats. Indian Journal of Experimental Biology 23: 402-403, July 1985, which is herein incorporated by reference in its entirety. Unfortunately, the use of creatine as an anti-inflammatory has been limited due to high dosage requirements, limited bio-availability characteristics, and as yet unknown interaction characteristics within the inflammatory response.
Consequently, it would be desirable to provide an anti-inflammatory compound which altered the inflammatory cascade at a point prior to cyclooxygenase activation of the arachidonic acid metabolites. Such a compound may avoid the harmful side effects, such as gastric and renal toxicity, associated with currently used anti-inflammatory agents. Further, it would be desirable to provide a method of delivering an anti-inflammatory compound, which enabled effective amounts of the active anti-inflammatory agent within the compound to reach the cell undergoing an inflammatory cascade and be modified into the active agent by the host system. Additionally, it would be desirable to provide a method of inhibiting prostaglandin synthesis, an arachidonic acid metabolite, during a cellular inflammatory cascade.
Still further, it would be desirable to provide an anti-inflammatory compound in tolerable dosages capable of altering the cellular inflammatory cascade and providing relief from associated inflammation, pain, swelling, fever, and the like. Finally, it would be desirable to provide pain relief through use of an anti-inflammatory creatine compound which is safer, more tolerable, and has increased bio-availability, for inhibiting inflammation and the inflammatory response.